Our original NIDCR grant (DE018701) developed guided tissue regeneration (GTR) scaffolds for the reconstruction of periodontitis-caused infrabony defects that employed a new non-antibiotic based concept in biomaterials that, for the first time, promoted both a short- and a long-term immune response to a specific oral bacterial pathogen, Porphyromonas gingivalis (PG). Using a novel templating technology, we can fabricate polymer porous templated scaffolds (PTS) where every pore is the same size and pore interconnects are also uniform in size, with both parameters being adjustable. If the pore size is ~35?m, PTS show remarkable healing in numerous soft and hard tissues; independent of the polymer used. Given that our original project created PTS that successfully prevent bacterial infection, we now turn our attention in this renewal to defining the underlying mechanisms governing the tissue regeneration observed only in the 35?m PTS. Our transformative research will first prove and then second develop the heretical concept that other myeloid cells, i.e., the macrophage, can be engineered to trans-differentiate into desired non-myeloid lineages. Considering the population size of macrophage cells within humans, ease of access, and the ethical issues related to stem cell research, directing macrophage differentiation, rather than stem cells, could create whole new science paradigms and regenerative medicine technologies.